title: The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.
abstract: The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p<0.01). Duodenal administration of polymeric micelles together with bile acids in bile duct ligated rats fully restored absorption. Dynamic light scattering time series showed a significant and dose dependent rise in micellar size in the presence of bile acids in vitro, indicating the gradual formation of mixed micelles during the first 3 h of incubation. The highest bile acid amounts (11 mM deoxycholic acid and 41 mM taurocholic acid) eventually caused aggregation of the loaded micelles after the formation of mixed micelles. These data suggest that the gastrointestinal absorption of encapsulated vitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.
authors.affiliation: Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. p.vanhasselt@umcutrecht.nl
authors.forename: P M
authors.initials: PM
authors.lastname: van Hasselt
authors.forename: G E P J
authors.initials: GE
authors.lastname: Janssens
authors.forename: T K
authors.initials: TK
authors.lastname: Slot
authors.forename: M
authors.initials: M
authors.lastname: van der Ham
authors.forename: T C
authors.initials: TC
authors.lastname: Minderhoud
authors.forename: M
authors.initials: M
authors.lastname: Talelli
authors.forename: L M
authors.initials: LM
authors.lastname: Akkermans
authors.forename: C J F
authors.initials: CJ
authors.lastname: Rijcken
authors.forename: C F
authors.initials: CF
authors.lastname: van Nostrum
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D001652:Bile Ducts / Q000601:surgery; D001682:Biological Availability; D004337:Drug Carriers / Q000737:chemistry; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects; D008026:Ligation; D008027:Light; D008297:Male; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012542:Scattering, Radiation; D014462:Ultrafiltration; D014812:Vitamin K / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014815:Vitamins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001647:Bile Acids and Salts; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D011109:Polymethacrylic Acids; D014815:Vitamins; C525969:poly(N-(2-hydroxypropyl)methacrylamide dilactate); D014812:Vitamin K; D011092:Polyethylene Glycols